ELK1 Promotes Epithelial-Mesenchymal Transition and the Progression of Lung Adenocarcinoma by Upregulating B7-H3

In previous studies, we found that B7 homolog 3 (B7-H3) was highly expressed in lung adenocarcinoma (LUAD) and promoted epithelial-to-mesenchymal transition (EMT) of LUAD cells. However, the underlying molecular mechanism is unclear. This study is aimed at evaluating the role of Ets-like protein 1 (ELK1) as a transcriptional regulator of B7-H3 for mediating the development and progression of LUAD in vitro and in vivo. We confirmed that ELK1 is highly expressed in LUAD and is associated with poor patient prognosis. ELK1 was found to promote proliferation, invasion, migration, and EMT of LUAD cells through in vivo and in vitro experiments. In terms of mechanism, ELK1 binds to the B7-H3 promoter region and induces the upregulation of B7-H3 in LUAD. Our data suggest that ELK1 plays an important role in the development of LUAD and could be used as a prognostic marker and therapeutic target for LUAD.

Delirium and Its Pharmacological Causes in Older People, Part Three

Delirium is a syndrome that can arise from many causes or underlying conditions, and though it has been reported in younger patients, it is more prevalent in older people, though it can occur in other age groups as well. Identifying delirium is challenging in older people because of the coexistence of underlying dementia or depression, which may further complicate the presentation. Drug-induced delirium is one of the major causes of delirium, and evaluation of this potential cause or contribution is an important component of the evaluation process, since it can lead to poor patient outcomes. Part one of this three part series reviewed the epidemiology, pathophysiology, evaluation, diagnostic process, and causes of delirium in older people. Parts two and three continued to review the pharmacological classes of medications that cause or contribute to delirium in older people.

PPM1D Is a Therapeutic Target in Childhood Neural Tumors

Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers.

High Rates of Bacterial Pulmonary Co-Infections and Superinfections Identified by Multiplex PCR among Critically Ill COVID-19 Patients

Background: The role of bacterial co-infection and superinfection among critically ill COVID-19 patients remains unclear. The aim of this study was to assess the rates and characteristics of pulmonary infections, and associated outcomes of ventilated patients in our facility. Methods: This was a retrospective study of ventilated COVID-19 patients between March 2020 and March 2021 that underwent BioFire®, FilmArray® Pneumonia Panel, testing. Community-acquired pneumonia (CAP) was defined when identified during the first 72 h of hospitalization, and ventilator-associated pneumonia (VAP) when later. Results: 148 FilmArray tests were obtained from 93 patients. With FilmArray, 17% of patients had CAP (16/93) and 68% had VAP (64/93). Patients with VAP were older than those with CAP or those with no infection (68.5 vs. 57–59 years), had longer length of stay and higher mortality (51% vs. 10%). The most commonly identified FilmArray target organisms were H. influenzae, S. pneumoniae, M. catarrhalis and E. cloacae for CAP and P. aeruginosa and S. aureus for VAP. FilmArray tests had high negative predictive values (99.6%) and lower positive predictive values (~60%). Conclusions: We found high rates of both CAP and VAP among the critically ill, caused by the typical and expected organisms for both conditions. VAP diagnosis was associated with poor patient outcomes.

The genotypic and phenotypic impact of hypoxia microenvironment on glioblastoma cell lines

Background Glioblastoma is a fatal brain tumour with a poor patient survival outcome. Hypoxia has been shown to reprogram cells towards a stem cell phenotype associated with self-renewal and drug resistance properties. Activation of hypoxia-inducible factors (HIFs) helps in cellular adaptation mechanisms under hypoxia. Similarly, miRNAs are known to be dysregulated in GBM have been shown to act as critical mediators of the hypoxic response and to regulate key processes involved in tumorigenesis. Methods Glioblastoma (GBM) cells were exposed to oxygen deprivation to mimic a tumour microenvironment and different cell aspects were analysed such as morphological changes and gene expression of miRNAs and survival genes known to be associated with tumorigenesis. Results It was observed that miR-128a-3p, miR-34-5p, miR-181a/b/c, were down-regulated in 6 GBM cell lines while miR-17-5p and miR-221-3p were upregulated when compared to a non-GBM control. When the same GBM cell lines were cultured under hypoxic microenvironment, a further 4–10-fold downregulation was observed for miR-34-5p, miR-128a-3p and 181a/b/c while a 3–6-fold upregulation was observed for miR-221-3p and 17-5p for most of the cells. Furthermore, there was an increased expression of SOX2 and Oct4, GLUT-1, VEGF, Bcl-2 and survivin, which are associated with a stem-like state, increased metabolism, altered angiogenesis and apoptotic escape, respectively. Conclusion This study shows that by mimicking a tumour microenvironment, miRNAs are dysregulated, stemness factors are induced and alteration of the survival genes necessary for the cells to adapt to the micro-environmental factors occurs. Collectively, these results might contribute to GBM aggressiveness.

The role of KPNA2 mutations in breast cancer prognosis: A survey of publicly available databases

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions. We report a survey of several publicly available databases probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing information available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival. Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents. In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.

Up-Regulation of YTHDF1 and YTHDF3 is Related to the Prognosis of Oral Squamous Cell Carcinoma

Background N6-methyladenosine (m6A) is the most abundant internal modification in mammalian mRNAs. M6A is composed of methyl-transferases, which act as ("writers"), binding proteins, which act as ("readers"), and demethylases, which act as ("erasers"). As an important part of ("readers"), YTHDF1 and YTHDF3 were shown to be associated with many cancers. This paper aimed to study the expression of YTHDF1 and YTHDF3 in oral squamous cell carcinoma (OSCC). Methods We detected the expression of YTHDF1 and YTHDF3 in 120 OSCC patients by immunohistochemical analysis. Statistical analysis was used to determine whether the high or low expression of these two genes was significantly associated with age, gender, histological type, clinical stage, or lymph node metastasis. The correlation curve and survival curve of the two genes were produced to evaluate the potential clinical significance. Results We find the expression of YTHDF1 and YTHDF3 was increased in OSCC tissues compared to adjacent normal tissues。The statistical analysis showed that the expression of YTHDF1 and YTHDF3 was significantly associated with the clinical stage and histological type in OSCC patients. There was also a significant correlation between the expression of YTHDF1 and YTHDF3. A high expression of YTHDF1 and YTHDF3 was related to poor patient prognosis. Conclusions Our findings suggest that a high expression of YTHDF1 and YTHDF3 may be related to poor patient prognosis.

The obstacles to combat against COVID-19 pandemic and the remedies: Bangladesh scenario

Background: Bangladesh has been going through the austerity of the unique COVID-19 for more than a year like several other nations in the world in spite of concerted efforts taken by the government along with other concerned authorities who have advocated compulsory guidelines involving social distancing procedures accompanied by lockdown to have control over the pandemic. In this paper, the barriers faced by the government to protect people from the COVID-19 pandemic have been investigated. Also, the number of daily infected people against the number of daily tests has been underlined to comprehend the overall pandemic picture in Bangladesh. Design and Methods: A descriptive study has been carried out to investigate the obstacles to tackle the COVID-19 pandemic for this country. The intensity of the outbreaks of the pandemic in this country is stated from March 8, 2020, to February 12, 2021. Secondary data have been employed from different sources to serve the goals of the study. Results: The poor management in the health sector of Bangladesh has been an issue of major concern during the early stage of COVID-19 which incorporates deficiency of medical equipment, lack of facilities for testing COVID-19, poor patient management, and uncertainty in the medication system. Finally, some recommendations have been proposed for the concerned organizations to tackle the current pandemic and as well in the future. Conclusions: To control this COVID-19 pandemic, it is necessary to find the difficulties and discover the remedies which have been done in this paper for the Bangladesh perspective.

Delirium and its Pharmacological Causes in Older People, Part Two

Delirium is a syndrome that can arise from many causes or underlying conditions, and though it has been reported in younger patients, it is more prevalent in older people, though it can occur in other age groups as well. Identifying delirium is challenging in older people because of the coexistence of underlying dementia or depression, which may further complicate the presentation. Drug-induced delirium is one of the major causes of delirium, and evaluation of this potential cause or contribution is an important component of the evaluation process, since it can lead to poor patient outcomes. Part one of this three part series reviewed the epidemiology, pathophysiology, evaluation, diagnostic process, and causes of delirium in older people, with a focus on the pharmacological causes. Part two of this series continues to review drugs and drug classes that can cause or contribute to delirium in older people.